[123I]-2β-carbomethoxy-3β-(4-flurophenyl)-N-(3-iodo-E-allyl) nortropane is potentially useful as an aid to diagnosing Parkinson's Syndromes (PS). Without being bound by any particular theory, PS is believed to be characterized by the loss of dopamine-producing neurons in the brain. The loss of dopamine-producing neurons is believed to begin long before symptoms of the disease actually present. Symptoms of PS are often similar to many other movement disorders. Consequently, misdiagnosis rates are high, with some reports of up to 50% misdiagnosis in the early stages. There is currently no available test that can clearly identify Parkinson's Syndromes, especially in early cases. A diagnostic for early stage PS has long been sought.
Without being bound by any particular theory, the dopamine transporter (DAT) is believed to play a significant role in physiological, pharmacological and pathological processes in the brain. The transport system is a primary mechanism for terminating the effects of synaptic dopamine, thereby contributing to the maintenance of homeostasis in dopamine systems. It has also been reported to be a principal target of cocaine in the brain. (Kennedy and Hanbauer, J. Neurochem. 1983, 41, 172 178; Shoemaker et al., Naunyn-Schmeideberg's Arch. Pharmacol. 1985, 329, 227 235; Reith et al., Biochem Pharmacol. 1986, 35, 1123 1129; Ritz et al., Science 1987, 237, 1219 1223; Madras et al., J. Pharmacol. Exp. Ther. 1989a, 251, 131 141; Bergman et al., J. Pharmacol. Exp. Ther. 1989, 251, 150 155; Madras and Kaufman, Synapse 1994, 18, 261 275).
The brain grouping formed by the caudate nucleus and the putamen is called the striatum. It constitutes the major target for the cortical afferents of the basal ganglia. The striatum reportedly has the highest levels of dopamine terminals in the brain. A high density of DAT is localized on dopamine neurons in the striatum and appears to be a marker for a number of physiological and pathological states. For example, in Parkinson's Syndromes, dopamine is severely reduced and the depletion of DAT in the striatum has been an indicator for Parkinson's disease (Schoemaker et al., Naunyn-Schmeideberg's Arch. Pharmacol. 1985, 329, 227-235; Kaufman and Madras, Synapse 1991, 9, 43-49). Consequently, early or pre-symptomatic diagnosis of Parkinson's Syndromes can be achieved by the quantitative measurement of DAT depletion in the striatum. (Kaufman and Madras, Synapse 1991, 9, 43-49). Simple and noninvasive methods of monitoring the DAT are quite important. Depletion could be measured by a noninvasive means such as brain imaging using a scintillation camera system and a suitable imaging agent (Frost et al., Ann. Neurology 1993, 34, 423 431; Hantraye et al., Neuroreport 1992, 3, 265-268). If possible, imaging of the dopamine transporter would also enable the monitoring of progression of the disease and of reversal of the disease such as with therapies consisting of implants of dopamine neurons or drugs that retard progression of the disease. We believe that a radiopharmaceutical that binds to the DAT might provide important clinical information to assist in the diagnosis and treatment of these various disease states.
The decay of the [123I] associated with the compound results in the release of a photon with an energy of 159 KeV. This photon easily (and relatively safely) passes through human tissues and bones and can be detected, often by using a radiation detector array in a Single Photon Emission Computed Tomography (SPECT) camera. With appropriate software an image of the site from which the radiation is emerging can be constructed. The image can be compared to images obtained from subjects without signs of Parkinson's Syndromes. A decrease in emission is presumptive evidence of a loss of dopamine transporter neurons, and potentially a diagnosis of Parkinson's Syndromes.
An effective imaging agent for the disorders described above will exhibit a specific binding affinity and selectivity for the transporter being targeted. In addition, for imaging agents based on radioactive emission, a minimum level of radioactivity is also pertinent. The level of radioactivity is expressed in three ways, specific activity, the concentration of radioactivity, and the total amount of radioactivity administered. In addition, to be a viable commercial product, the radiochemical yield must be reasonable.
Specific activity, in this context, refers to the proportion of 2β-carbomethoxy-3β-(4-flurophenyl)-N-(3-iodo-E-allyl) nortropane molecules that have 123I as opposed to 127I, the non-radioactive iodine isotope. In order to obtain the maximum amount of signal per bound radiochemical molecule, the radiochemical procedure needs to be free of non-radioactive sodium iodide. In radiolabeling 2β-carbomethoxy-3β-(4-flurophenyl)-N-(3-tributyltin-E-allyl) nortropane with 123I-sodium iodide, the chemical amount of 123I is extremely small relative to the amounts found in ordinary chemical reactions. Special expertise and experience are generally required to achieve high-yield radio-labeling reaction conditions, and optimizing the conditions requires experimentation. In addition the optimization of the process is particularly expensive at large scale and requires special precautions due to the large amounts of radioactivity.
The concentration of the radiochemical and its stability are key factors in the successful commercial viability of radio-chemicals. The radiochemical and chemical stability of each uniquely structured radio-labeled entity is unpredictable from the structure alone. Furthermore, the effect of additives meant to increase stability cannot be known in advance of experimental testing. In addition, for those compounds with short half-life isotopes such as the one discussed herein, the shelf life is usually directly related to the concentration of the product. So long as the compound is stable to the effects of the additional radiation, the shelf life can be extended by using a higher the concentration of the compound. In this regard, [123I]2β-carbomethoxy-3β-(4-flurophenyl)-N-(3-iodo-E-allyl) nortropane may be more useful if it can be produced in sufficiently high concentrations such that it would still be emitting at suitable levels for a longer useful period of time. Periods for detectable emissions of one or two days, or longer, after creation are noted.